Post on 01-Feb-2016
description
Cardiovascular Cell Therapy: What’ s New?On Clinical Scenarios and Clinical Trials
Stefan P. Janssens, MD, PhD
Department of Cardiology
University of Leuven, Belgium
Madrid, April 24th, 2008No disclosures
30 years later: VALIANT study(14,703 post-MI pts EF<35%, clin CHF)
1 y mortality
1 y death, re-MI, CHF rehosp
Pfeffer et al . NEJM 2003
Cardiac Regeneration in 2008: the stem cell approach
Premise: myocyte deficit contributes to dysfunctional phenotype?
Caulfield et al . Circ 1976
Infarct size(% LV mass)
Shock, Death CHF
48% 28%
13%
26%
Stem Cells: from Bench to Bedside Clinical Scenarios
Stem Cells: from Bench to Bedside Clinical Scenarios
1. Acute Myocardial Infarction with significantly impaired LV function:
- is safety & efficacy sufficiently established to start a Phase IIIrandomized, controlled outcome trial?
or
- are additional innovative, mechanistic Phase II studies required?
5
Stem Cell Therapy in Post-MI Patients with Depressed LV Function is Safe
BOOST LEUVEN ASTAMI REPAIR-AMI
Follow-up (months) 18 12 12 12
Control/Placebo n=30 C n=34 P n=50 C n=103 P
Mortality 1 (3%) 0 0 6 (6%)
Reinfarction 0 1 0 6 (6%)
Revascularisation 4(13%) 2(6%) 11(22%) 37(36%)
BMC group n=30 n=33 n=50 n=101
Mortality 0 2(6%)# 0 2(2%)
Reinfarction 1(3%) 1(3%) 1(2%) 0
Revascularisation 5(17%) 2(6%) 13(26%) 22(22%)
(Adapted from Arnesen et al. Lancet 2007;369,2142)# unrelated to BMC
RC Trials using Intracoronary BMC post MI
LEUVEN-AMI
MI size
-28%(P=0.03)
ND
ND
P=n.s.
ND
+ 2.8% (P=n.s.)*
* 18-months follow-up
Stem Cells: from Bench to Bedside
Clinical Scenarios
What does an increase in global LVEF of a few % points mean?
Infarct Size Reduction in Reperfused STEMI
Infarct SizeReduction (%)
Small Infarcts(<17% LV mass)
Large Infarcts(>17% LV mass)
Small Infarcts (n=29)
LargeInfarcts(n=29)
Age 58±11 61±11
BP adm 140/82 128/80*
LV-EDP 18±5 26±8 **
IRA
LAD 11 15
RCA 17 12
Cx 1 2
Time to PCI 284±180 292±173
Max Trop 60±28 115±68 **
Meds ACE-/BB/Stat/Asp
ACE-/BB/Stat/Asp
Infarct Size Determines Global and Regional Functional Recovery in Reperfused STEMI
Change in LV-EF (%)
Small Infarcts(<17% LV mass)
n=29
Large Infarcts(>17% LV mass)
n=29
Δ+ 3%P=0.003
P=NS
SWT(mm)
Small Infarcts(<17% LV mass)
n=29
Large Infarcts(>17% LV mass)
n=29
Border Infarct BorderInfarct
P=0.01
P=0.003
P=NS
P=NS
Bone Marrow Cell Transfer Post-AMI Infarct size and Coronary Flow Reserve (Doppler)
(Schachinger et al., NEJM 2006; 355:1210-21)
BMCPlac
20
-20
10
-10
0
<48.9% >48.9%
P=0.002
P=0.81
(52) (41) (40) (54)
Baseline EF (%)
Δ EF (%)
(Erbs et al., Circulation 2007)
(n=30) (n=28)
Infarct Size Determines Global Functional Recovery in Reperfused STEMI
Change in LV-EF
(%)
Large Infarcts(>20% LV mass, n=20)
Change in LV-ESVI
(mL)
CON
BMSC
Baseline Baseline1 year 1 year
P=0.06 for interaction
P=0.07 for interaction
44
48
43 45
Wall Motion Score Index and Ejection Fraction for Risk Stratification after AMI
Predictors of mortality(forward Cox PHA)
HR P
Age (per 10y) 1.65 <.0001
Kilip Class 1.44 <.0001(per 1 increase)
WMSI 1.15 <.0001(per 0.2 increase)
(Moller et al. Am Heart J 2006;151:419-25)
Powerful MRI and TDI Analysis of Biological Signals: Infarct Transmurality & Segmental Contraction
Coronary occlusion
20 min 60 min 3h >6h
LV
apexapex
midmidbasebase
Time (ms)
-20
-10
0
0 200 400 600 800 1000
Strain Septum 4 months (%)
-30
AVCAVCAVOAVO
-20
-10
0
200 400 600 800
-30
AVCAVCAVOAVOBaseline Strain Septum (%)
Improved contraction (%)
0
20
40
60
80
CONTROL BMC
(29 o
f 53)
(33 o
f 63)
(14 o
f 32)
(25 o
f 83)
(6 o
f 13)
(9 o
f 18)
(9 o
f 25)
(10 o
f 87)
Improved Regional Contraction in Dysfunctional Segments indicates BMC Functional Repair
Lancet 2006; 367:113-121
-20
-15
-10
-5
0Baseline 5 d 2 mo 4 mo 1 yr
(n=232)Infarcted segments
*** ***
ES Strain(%)
BMSC
Control
0-25
%
26-5
0%
51-7
5%76
-100
%
0-25
%
26-5
0%51
-75%
76-1
00%
P<0.05 for interaction
*
*
Schachinger, V. et al. Eur Heart J 2006 27:2775-2783
Kaplan-Meier event-free survival analysis
Cardiac Regeneration in 2008: Clinical Scenarios
VALIANT study(14,703 post-MI pts EF<35%, clin CHF)
1 y mortality
1 y death, re-MI, CHF rehosp
Pfeffer et al . NEJM 2003
13%
26%
Power calculations for Outcome study:
Significant Reduction incombined Clinical EP(death, recurrent MI, CHF hospitalizations)requires ± 1,200 pts
Bone Marrow Cell Therapy Anno 2008:Limitations for Cinical Benefit
• Modest improvement in cardiac function in 4 RCTs of BMC transfer is attributable to:
– limited homing, engraftment, and survival of BMCs
lack of cardiac muscle regeneration
IC injection18F-FDG labeled BMSC:1.3 - 2.6% homing infarct region (Hofmann et al. Circ 2005)
limited progenitor cell functionality in sick patients
Stem Cells: from Bench to Bedside Clinical Scenarios
Stem Cells: from Bench to Bedside Clinical Scenarios
2. Acute myocardial infarction with significantly impaired LV function:
- Focus on cell enhancement strategies- Labeling and in vivo tracking of different progenitor cell populations
1. luciferase bioluminescence2. Genetic or histochemical marker (GFP, Endorem, DiI, ..)3. PET/CT: compare timing of delivery and route of administration
1. Acute Myocardial Infarction with significantly impaired LV function:
- clinical outcome trial (phase III, confirmed safety & efficacy) versus- innovative, mechanistic studies (phase II)
Stem Cells: from Bench to Bedside Cell Enhancement Strategies
Priming of Progenitor Cells
Priming of Target Tissue
Impaired PC phenotype & non-responders:
~ CV Risk factors ~ progenitor cell
modification
Hostile target milieu: ~ oxidant stress ~ microvascular obstruction ~ transmigration - residency
BMC and EPC cell transfer3 hours after I/R
I/R injury
L2G85 FVB
WT FVB
Hypothesis
Imaging of Bone Marrow Mononuclear Cell Homing in Ischemic Myocardium
Click # OG20080123115158Wed, Jan 23, 2008 11:52:12Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -16785Max = 26578p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080123120324Wed, Jan 23, 2008 12:03:37Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -18712Max = 18897p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080124142858Thu, Jan 24, 2008 14:29:11Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -13791Max = 17409p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080124142858Thu, Jan 24, 2008 14:29:11Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -13791Max = 17409p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080126094558Sat, Jan 26, 2008 09:46:11Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -37348Max = 28949p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080126094558Sat, Jan 26, 2008 09:46:11Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -37348Max = 28949p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080128142157Mon, Jan 28, 2008 14:22:10Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -9926.4Max = 56148p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080128142157Mon, Jan 28, 2008 14:22:10Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -9926.4Max = 56148p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080130144113Wed, Jan 30, 2008 14:41:27Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -9422.3Max = 43789p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080130144113Wed, Jan 30, 2008 14:41:27Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -9422.3Max = 43789p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080201113245Fri, Feb 01, 2008 11:32:58Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -34455Max = 57144p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080201113245Fri, Feb 01, 2008 11:32:58Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -34455Max = 57144p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080205141239Tue, Feb 05, 2008 14:12:52Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: exp pilot cardiac homing fvbxfvbExperiment: Label: day 14Comment: 6452-6453-6455-6457Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -12149Max = 32202p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080205141239Tue, Feb 05, 2008 14:12:52Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: exp pilot cardiac homing fvbxfvbExperiment: Label: day 14Comment: 6452-6453-6455-6457Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -12149Max = 32202p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080212104851Tue, Feb 12, 2008 10:49:04Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: exp pilot cardiac homing fvbxfvbExperiment: Label: day 21Comment: 6452-6453-6455-6457Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -15802Max = 18214p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080212104851Tue, Feb 12, 2008 10:49:04Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: exp pilot cardiac homing fvbxfvbExperiment: Label: day 21Comment: 6452-6453-6455-6457Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -15802Max = 18214p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmicDay 1 Day 2 Day 6Day 4 Day 8 Day 10 Day 14 Day 21
Click # OG20080123115158Wed, Jan 23, 2008 11:52:12Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -16785Max = 26578p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
Click # OG20080123115158Wed, Jan 23, 2008 11:52:12Bin:M (8), FOV25, f1, 5mFilter: OpenCamera: IVIS 175, SI620EEV
Series: Experiment: Label: Comment: Analysis Comment:
30000
25000
20000
15000
10000
5000
ImageMin = -16785Max = 26578p/sec/cm^2/sr
Color BarMin = 2000
Max = 30000
bkg subflat-fieldedcosmic
I/R
Sham
Reperfusion Therapy frequently Associated with Microvascular Obstruction (MVO)
Cx occlusion
Successful PCI
Incidence postPCI: >60%
Persistent MVO
J. Bogaert & S. Janssens, Eur J Rad 2007
47 (9)
4 mo
46 (8)
LV-EF (%)
P=NS
3-4 d
LV-EDV (mL)
P=0.014162 (33) 175 (43)
3-4 d 4 mo
BMSC (n=17)
CON (n=19)
MVO
Global LV Function Recovery in AMI Patientswith and without Microvascular Obstruction
44
46
48
50
52
54
56
58
60
62
1 week 4 months
P = 0.63
P = 0.60
LV-EF (%)
12 months
BMSC (n=11)
CON (n=9)
No MVOP = 0.05
P = 0.36
+3.5%
+5.5%
Direct Labeling of Stem Cells Using Positron Emission Tomography Radionuclides
• T1/2 = 109 min
• Transport via GLUT
• Phosphorylated by hexokinase
(= metabolic trapping)
• Good labeling efficiency
• Poor retention
• Substrate for cardiomyocytes
2-[18F]fluorodeoxyglucose (FDG)
(Ma et al. 2005)
90 min postinjection
60 min postinjection
30 min postinjection
Liver
Heart
Bladder
Direct Labeling of Stem Cells Using Positron Emission Tomography Radionuclides
• T1/2 = 109 min
• No transport, no enzymatic reaction
• Incorporation in cell membrane
• Good labeling efficiency
• Good retention
• No substrate for cardiomyocytes
Hexadecyl-4-[18F]fluorobenzoate (HFB)
(Ma et al. 2005)
LiverHeart
Bladder
18F-HFB
90 min postinjection
60 min postinjection
30 min postinjection
18F-HFB BMCs vs Free label Injection post MI
Stem Cells: from Bench to Bedside Cell Enhancement Strategies
Priming & Labeling of Progenitor cells
• statins• p38 inhibitors• PPAR• eNOS enhancers• Integrin activators• Cardiac specification….• gene transduction: Akt, eNOS,
…• PET- MRI tracers
• Mechanical activation • Cytokines / Growth
factors: – IGF-1, HGF, SDF-1, PDGF,….
• NO
Priming of Target Tissue
Impaired EPC phenotype & non-responders ~ CV Risk factors ~ post MI cell modification
Hostile target milieu ~ oxidant stress ~ microvascular obstruction ~ transmigration - residency
Stem Cells: from Bench to BedsideInformative Cell Delivery Studies
• REGENT Poland (NCT 00313339) - recruitment completeR, open label, safety/efficacy: BMNC vs CD34+/CxCR4+ vs CON post AMI (EF<40%)Prim EP: LVEF and volumes (Echo and angio) ---> 2008?
• SWISS AMI (NCT 00355186)
(EF<45%, IC transfer at 5-7d vs 3-4 w, MRI analysis LVEF) ---> evaluate after 60
• MYSTAR Austria (NCT 00384982)
(4 arm 360 pts, LVEF<45%, comp 21-42 d vs 3 mo post-AMI and IC vs IM delivery vs combination)Prim EP: perfusion defect and LVEF by gated SPECT, NOGA ---> 2008 - 2009?
• AMORCYTE REPAIR US (NCT 00313339)
(Ph I, CD34+ cells post AMI, n=40)
(www.ClinicalTrials.gov)
Stem Cells: from Bench to BedsideInformative Cell Delivery Studies
• REVEAL US (NCT 00378352) Ph I/II: dose finding -> RCT Db blind, safety/efficacy: EPCs vs CON post AMIPrim EP: Infarct size (MRI), n=210
• NEURONYX US (NCT 00361855) & PROVACEL Osiris, US (NCT 00114452)
Ph I, RCT, safety escalating doses allogeneic hBM-derived SCs-MSC n=18 and 48
• MAGIC-Cell-5-Combicytokine (Korea, ± 120 pts, 1:1:2)Ph II, RCT: safety/efficacy CON vs G-CSF+MN Cell apheresis vs G-CSF+MN Cells + EPO
• CHF or Chronic refractory ischemia - Surgery:– BMNC during CABG Berlin (NCT 00462774)
60 pts, CD133+ cells in infarct border zone LVEF<35%), MRI EP: LVEF - Refractory ischemia Kobe (NCT 00221182)
10 pts, CD34 + cells IC, sestamibi SPECT scans- BMNC and CABG for CHF Helsinki (NCT 00418418)
RCT, dble blind, efficacy; Incl if CABG and EF 15-45%; prim EP: LVEF by MRI at 6 mo- TABMMI Biocardia endocardial delivery chronic infarcts Argentina (NCT 00507468)
Ph I , safety, prior AMI with LVEF<40%, n=20 pts
(www.ClinicalTrials.gov)
Sca-1+ cellsc-Kit + cells
SP cells
Endothelial Progenitor Cells
Hematopoietic SCsMesenchymal SCs
HemangioblastsSP cellsMAPC
Sca-1+ cellsMyoblastsSP cells
Mesenchymal SCsSPcells
PLURIPOTENT
Acute MI
Chronic Ischemia
Cardiac Stem Cells
Cardiac Stem Cells
• Revascularisation using CSC US Kentucky (NCT 00474461)
- Ph I: n=40; - RAA resection during CABG - Reinfusion of CSC after 4 mo if LVEF < 40%
Anversa P.et al. Circulation 2007
Acknowledgments
- X. Liu, MD, PhD- P. Pokreisz, PhD- T. Vandendriessche - M. Chua- K. Sipido, MD, PhD
- C. Dubois, MD- G. Marsboom, PhD- O. Gheysens, MD- S. Vandenwyngaert, MSc- H. Gillijns, BSc- M. Pellens, BSc
Cardiology lab and CTG SCIL- C. Verfaillie, MD, PhD- M. Boogaerts, MD, PhD- L. Mortelmans, MD, PhD
KUL & Univ Hospital
- F. Van de Werf, MD, PhD- G. Marchal, MD, PhD- J. Bogaert, MD, PhD- G. Bormans, PhD- A. Verbruggen, MD, PhD
Stanford University- S. Gambhir, MD, PhD
Harvard University- K. Bloch, MD
Conclusions
Modest effects of BM-derived progenitor cell transfer in AMI is likely attributable to limited homing and engraftment and lack of cardiomyogenesis.
Comprehensive 3D-MRI analysis suggests early infarct imaging correlates with diverging patterns of functional and structural recovery post-MI.
Progenitor cell transfer is best reserved for patients with large MI, at risk for developing maladaptive remodeling and heart failure. Potential confounding factors including MVO and cell functionality, warrant focused trials.
Stem Cells: from Bench to Bedside Cell Enhancement Strategies
Stem Cells: from Bench to Bedside Cell Enhancement Strategies
1. Labeling and (in vivo) tracking of different progenitor cell populations• In vivo tracking:
- luciferase bioluminescence- PET/CT
• Genetic marker (Lentiviral infection GFP, RFP,..)• Histochemical labeling (Endorem, DiI, …)
2. Factors limiting Functionality/Survival of progenitor cell populations (hypoxia and tissue ischemia) (microvascular obstruction)